CXCR4 Chemokine Receptor regulation of ERK MAP Kinase

描述(由申请人提供)：T淋巴细胞的激活和迁移是正常免疫功能的关键，T淋巴细胞抗原受体-CD3复合体(TCR)和趋化因子受体(如CXCR4)的信号广泛交叉调节。例如，CXCR4共刺激TCR刺激的T淋巴细胞的免疫激活，而TCR信号则取消CXCR4介导的迁移，并参与CXCR4介导的T淋巴细胞感染人类免疫缺陷病毒1(HIV-1)。尽管有证据表明TCR和CXCR4信号通路在重要方面相互调节，但T淋巴细胞中的CXCR4信号通路尚不完全清楚。此外，据我们所知，关于趋化因子或CXCR4和TCR交叉调节的分子机制还没有详细的研究报道。我们最近的结果表明，CXCR4信号调节T淋巴细胞表面CXCR4和TCR之间的紧密结合，并通过一种需要TCR和TCR相关信号分子的机制激活ERK MAPK。因此，我们提出的实验将填补当前知识的这一空白，通过测试中心假设，即T细胞中的CXCR4信号通过一种新的机制，涉及CXCR4与TCR相关联，并使用TCR进行信号转导。我们的具体目的是(1)了解CXCR4和TCR之间的相互作用是否具有特异性；(2)CXCR4信号如何调节CXCR4/TCR复合体及其移动到信号发生的亚细胞室；(3)CXCR4是否使用TCR和其他信号蛋白来激活ERK和共刺激TCR信号。这些研究的结果将描述T细胞中CXCR4信号的新机制，这对CXCA4介导的基因表达是重要的，也可能有助于CXCR4介导的T细胞激活和HIV-1病理生物学的协同刺激。此外，无论最终是否发现CXCR4/TCR复合体具有生物学相关性，这些实验都将解决受体如何寡聚以及如何从亚细胞内发出信号的基本问题。最后，这些实验将确定可用于严格测试CXCR4/TCR复合体调节T淋巴细胞生物学功能的试剂。因此，这些研究的结果将为更好地理解和操纵T细胞免疫激活和T细胞迁移之间的相互作用提供理论框架。

DESCRIPTION (provided by the applicant): T lymphocyte activation and migration are critical for normal immune functions, and signaling by the T lymphocyte antigen receptor-CD3 complex (TCR) and chemokine receptors such as CXCR4 are extensively cross regulated. For example, CXCR4 costimulates the immune activation of TCR-stimulated T lymphocytes, while TCR signaling abrogates CXCR4-mediated migration and participates in CXCR4-mediated infection of T lymphocytes with the Human Immunodeficiency Virus-1 (HIV-1). Despite evidence that TCR and CXCR4 signaling pathways cross-regulate in important ways, CXCR4 signaling pathways in T lymphocytes are incompletely characterized. Moreover, to our knowledge, no detailed studies on the molecular mechanisms of chemokine or CXCR4 and TCR cross-regulation have been reported. Our recent results demonstrate that CXCR4 signaling regulates a close association between CXCR4 and TCR on the surface of T lymphocytes, and activates the ERK MAP kinase via a mechanism requiring the TCR and TCR associated signaling molecules. Our proposed experiments will therefore fill this gap in the current knowledge, by testing the central hypothesis that CXCR4 signals in T cells via a novel mechanism that involves CXCR4 associating with the TCR and using the TCR for signal transduction. Our specific aims are to (1) ask if the interaction between CXCR4 and the TCR is specific, (2) ask how CXCR4 signaling regulates the CXCR4/TCR complex and its movement into subcellular compartments where signaling takes place, and (3) ask if CXCR4 uses the TCR and other signaling proteins for ERK activation and costimulation of TCR signaling. The results of these studies will characterize novel mechanisms of CXCR4 signaling in T cells that are important for CXCA4-mediated gene expression, and that probably also contribute to CXCR4-mediated costimulation of T cell activation and HIV-1 pathobiology. In addition, whether or not the CXCR4/TCR complex is eventually found to have biological relevance, these experiments will address basic questions of how receptors oligomerize, and signal from within, subcellular compartments. Finally, these experiments will identify reagents that can be used to rigorously test the idea that CXCR4/TCR complexes regulate T lymphocyte biological functions. The results of these studies will therefore serve as a theoretical framework for better understanding and manipulating the interplay between T cell immune activation and T cell migration.